Alzheimer's Disease
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that primarily affects the elderly. In 1984, Blass and Zemcov (Blass and Zemcov 1984) proposed that AD resulted from a decreased metabolic rate in sub-populations of cholinergic neurons. However, it has become clear that AD is not restricted to cholinergic systems, but involves many types of transmitter systems, and several discrete brain regions. The decreased metabolic rate appears to be related to decreases in glucose utilization. Brain imaging techniques have revealed decreased uptake of radiolabeled glucose in the brains of AD patients, and these defects can be detected well before clinical signs of dementia occur (Reiman, Caselli et al. 1996). Measurements of cerebral glucose metabolism indicate that glucose metabolism is reduced 20-40% in AD resulting in critically low levels of ATP.
The cause of the decreased glucose metabolism remains uncertain, but may be related to processing of the amyloid precursor protein (APP). Mutations that alter the processing of APP have been implicated in early onset AD. Early onset cases occur before the age of 60 and in many cases have been associated with mutations in three genes: APP, presenilin 1 (PS1) and presenilin 2 (PS2). Mutations in these genes lead to aberrant processing of the APP protein (for review see (Selkoe 1999)). Where examined, these pathological mutations result in early defects in cerebral glucose metabolism. Individuals harboring a double mutation at APP670/671 (the “Swedish mutation”) exhibit pathological decreases in glucose metabolism in temporal lobes, often before clinical manifestations of dementia are evident. Mice carrying an APP V717F transgene exhibit regional defects in cerebral glucose metabolism. Also, mutations in the presenilin genes may directly increase susceptibility to glucose deprivation.
Attempts to compensate for reduced cerebral metabolic rates in AD have met with some success. Elevation of serum ketone body levels in AD patients raises cognitive scores (Reger, Henderson et al. 2004) and USP. However, this reported method requires administration of large amounts of fat to generate the sufficient levels of ketone bodies. Therefore, a need exists for compounds that can elevate ketone levels without large fat consumption.
Parkinson Disease (PD)
Parkinson's disease (PD) is a progressive neurodegenerative disorder that is the second most common neurodegenerative disease after Alzheimer's disease. The estimated prevalence of PD is 0.3 percent in the general U.S. population and a prevalence of 4 to 5 percent in those older than 85 years. PD is characterized by motor abnormalities, including tremors, muscle stiffness, lack of voluntary movements, and postural instability. A primary neuropathological feature of PD is the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of eosinophilic intracytoplasmic inclusions (Lewy bodies) in the residual dopaminergic neurons.
Current treatments for PD include monoamine oxidase-B (MAO-B) inhibitors, amantadine (Symmetrel), or anticholinergics. Such agents may modestly improve mild symptoms. However, due to large scale cell loss the American Academy of Neurology (AAN) recommends levodopa or a dopamine agonist when dopaminergic treatment is required. Typically, levadopa is given to those who need to improve motor disability, while dopamine agonists are given to those who need to decrease motor complications. In general, a dopamine agonist is initiated in younger patients with mild disease, whereas levodopa is initiated in older patients with severe motor symptoms.
While treatment for PD in the early stages can be considered relatively successful, after about five years of treatment with levodopa, about 40 percent of patients develop dyskinesia (i.e., involuntary choreiform or stereotypic movements involving the head, trunk, limbs, and, occasionally, the respiratory muscles). Patients experience a “wearing-off” effect characterized by a weakening of the benefit from individual levodopa doses, causing the parkinsonian symptoms to reemerge. Patients may also experience an “on-off” effect characterized by unpredictable, abrupt fluctuations in motor state. Therefore, there exists a need for more effective treatments for PD and in particular for treatments that are neuroprotective.
While the cause of sporadic PD is uncertain, several lines of evidence suggest that defects in oxidative phosphorylation may contribute to its pathogenesis. For example, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), blocks complex I (NADH-ubiquinone oxidoreductase) of the mitochondrial electron transport chain, and causes the loss of dopaminergic neurons and the typical symptoms of PD. Reduction in complex I activity has also been reported in PD tissues. This defect is not confined only to the brain but has also been found in platelets from PD patients.
D-β-Hydroxybutyrate (BHB) is a ketone body produced by hepatocytes and, to a lesser extent, by astrocytes. BHB acts as an alternative source of energy in the brain when glucose supply is limited such as during starvation. BHB has been found to protect from MPTP-related complex I inhibition, by enhancing oxidative phosphorylation {Tieu, 2003#295}.
Friedreich's Ataxia (FRDA)
FRDA is a recessive disease characterized by progressive ataxia, hypertrophic cardiomyopathy, early onset of insulin-resistant diabetes, invalidism, and premature death. FRDA is a genetic disorder caused by a deficiency of frataxin, a 210 amino acid nuclear-encoded mitochondrial protein. Low levels of the protein are due to the expansion of an intronic GAA repeat, leading to decreased mRNA levels. FRDA patients show a decrease in the activity of the mitochondrial enzyme aconitase. Aconitase is responsible for conversion of citrate to isocitrate, the first step in the Krebs (also known as the citric acid or TCA cycle). Deficiency of frataxin in human patients is thought to lead primarily to defects in the TCA cycle.
Recent work shows that elevation of blood ketone bodies, a normal response to fasting, can increase mitochondrial citrate and isocitrate levels, thus overcoming the block in aconitase found in FRDA. A ketone body-based therapy could provide an effective treatment for this group of patients.
GLUT1-Deficient Epilepsy
GLUT1-deficient Epilepsy is characterized by infantile seizures, delayed development, and acquired microcephaly with mental retardation. GLUT1-deficient epilepsy results from several types of mutation in the gene of GLUT1. Glucose transporter 1 (GLUT1) is the major protein responsible for the transport of glucose from bloodstream into the brain. Under standard dietary conditions, the brain is almost entirely dependent upon blood glucose for energy. However, under some circumstances, such as starvation, ketone bodies can provide a source of energy different from glucose. Ketone bodies do not rely on GLUT1 for transport into the brain and therefore may provide energy in GLUT1-deficient syndrome. Ketone body therapy may therefore become a practical method for lifelong treatment of these patients.
Leprechaunism and Rabson-Mendenhall Syndrome
Leprechaunism and Rabson-Mendenhall syndrome are rare disease characterized by insulin resistance, persistent hyperglycemia and retardation of growth. Subjects rarely survive past 20 years of age. These syndromes result from mutations in the insulin receptor gene, which lower the receptors affinity for insulin. The current treatment consists of administration of increasing doses of insulin (up to several thousand units per day). This treatment yields only weak results due to the poor binding of insulin to its receptor. Ketone bodies have been shown to mimic the effects of insulin's stimulation of the PDH multienzyme complex, thereby increasing the Krebs TCA cycle metabolite levels, increasing the energy output in the form of ATP, and enhancing metabolic efficiency. A ketone-rich, or ketogenic diet may prove an effective treatment of these conditions
Other Diseases and Syndromes
A great number of other diseases and syndromes are associated with decreased metabolism. Such conditions include Coronary Arterial Bypass Graft (CABG) dementia, age associated memory impairment, anesthesia induced memory loss, Traumatic brain injury, Huntington's disease and many other. It is apparent that a metabolic intervention may aid people suffering from such afflictions.
Unmet Need
While ketone body based therapies may be appropriate for such diseases, current methods are impractical or inadequate. Ketogenic diets require continuous strict adherence to low carbohydrate intake which makes them difficult to comply with.
In 1979 Birkhahn et al., ((Birkhahn, McMenamy et al. 1979)) described the synthesis of the monoglyceride of acetoacetate which they called monoacetoacetin (MA). In subsequent studies (1986), Birkhahn, McMemany and Border fed monoacetoacetin intravenously to rats to examine if monoacetoacetin was a suitable replacement energy source (Birkhahn, Askari et al. 1986).
Additional studies on monoacetoacetin were done by Hirakawa and co-authors extending work by Birkhahn. In a study published in 2004 Sawai et. al. examined the effect of monoacetoacetin as a source of energy for cell cultures of several gastric cancer cell lines. (Sawai, Yashiro et al. 2004) (Takahata, Ohira et al. 2004).
It can be seen that none of the published prior art relates to the use of monoacetoacetin for the treatment of neurological disorders such as Alzheimer's disease, Parkinson's disease, Friedreich's Ataxia (FRDA), GLUT1-deficient Epilepsy, Leprechaunism and Rabson-Mendenhall Syndrome, Coronary Arterial Bypass Graft (CABG) dementia, anesthesia induced memory loss, age associated memory impairment, Traumatic brain injury, Huntington's disease or Parkinson's disease. It is the novel insight of the present invention that monoacetoacetin could be used to treat such conditions.
Several patent applications were filed on related compounds by Birkhahn and co-inventors. U.S. Pat. No. 5,420,335 entitled “Parenteral nutrients based on water soluble glycerol bisacetoacetates” was issued on May 30, 1995. U.S. Pat. No. 5,693,850 entitled “Nutritive water soluble glycerol esters of hydroxybutyric acid” was issued Dec. 2, 1997. A series of patents and applications relate to similar compounds for the treatment of neurodegenerative disorders by the inventor Richard Veech, these include U.S. Pat. Nos. 6,323,237, 6,316,038, and 6207856 as well as several applications including: US2004/0266872, US2004/0171671 and US2006/0280721. However, it is noted that the Veech patents teach that since “neither 1,3 butanediol, which forms acetoacetate, nor glycerol, which is a precursor of glucose, is part of the normal redox couple, D-β-hydroxybutyrate” and that “a physiological ratio of ketones should be given. If it is not, in the whole animal, the liver will adjust the ratio of ketones in accordance with its own mitochondrial free [NAD+]/[NADH]. If an abnormal ratio of ketones is given pathological consequences are a distinct possibility”. See, e.g., US2004/0171671 Paragraph [0054].
Therefore, it can be seen that the present invention shows that monoacetoacetin and other acetoacetate esters, administered in the lack of a source of hydroxybutyric acid or corresponding salt, may be used to effectively treat neurodegenerative disorders. Therefore, the unmet needs discussed above may be addressed.
All U.S. patents and patent applications referenced herein are incorporated by reference herein in their entireties. A partial list of those patents and applications referenced herein include, for example, U.S. Ser. No. 60/953,074, “Genomic testing in Alzheimer's disease and other diseases associated with reduced neuronal metabolism”, filed Jul. 31, 2007; U.S. Ser. No. 60/917,886, “Inhibitors of Acetyl-CoA Carboxylase for Treatment of Hypometabolism”, filed May 14, 2007; U.S. Ser. No. 11/123,706, “Method for Reducing Levels of Disease Associated Proteins”, filed May 3, 2005; U.S. Ser. No. 11/424,429, “Method To Reduce Oxidative Damage And Improve Mitochondrial Efficiency”, filed Jun. 15, 2006; U.S. Ser. No. 10/546,976, “Novel-Chemical Entities and Methods for their Use in Treatment of Metabolic Disorders”, filed Aug. 25, 2005; U.S. Ser. No. 09/845,741, filed May 1, 2001; U.S. Ser. No. 10/152,147, filed Dec. 28, 2004, now U.S. Pat. No. 6,835,750; U.S. Ser. No. 11/021,920, filed Dec. 22, 2004; U.S. Ser. No. 11/331,673, filed Jan. 13, 2006; U.S. Ser. No. 11/611,114, filed Dec. 14, 2006; and U.S. Ser. No. 11/771,431, filed Jun. 29, 2007.